Spreading depolarization induced by amygdala micro-injury prevents disruption of fear memory extinction in rats.

Spreading depolarization (SD), a self-propagating wave of near-complete breakdown of the transmembrane ion gradients with water influx, regularly occurs in traumatized human brain. Here, we investigated long-term neurobehavioral consequences of injury-triggered SDs. Recently, we revealed that SD is reliably triggered by micro-injury of the amygdala, a key brain structure involved in fear processing. Using the classical Pavlovian fear conditioning paradigm, we investigated effects of the post-retrieval amygdala micro-injury and associated SD on fear memory in rats. We found that neither SD nor micro-injury alone affect fear response 24 h later but profoundly change it in subsequent extinction phase. If bilateral injury of the amygdala did not induce SD, fear extinction was severely impaired, while conditioned fear in rats with the identical amygdala injury triggering SD was successfully extinguished similarly to naïve rats. Our study provides first experimental evidence for involvement of injury-induced SD in extinction of traumatic fear memory.

Small damage of brain parenchyma reliably triggers spreading depolarization.

Objectives: Spreading depolarization (SD) is a well-recognized component of the stress response of the cortex to its acute injury. Cortical SD has been shown to occur in severe brain insults and standard neurosurgical procedures in patients and is supposed to promote delayed secondary brain injuries. Stereotactic surgery and site-specific intracerebral microinjections produce a small tissue injury when a thin needle is inserted directly into the brain parenchyma (via the cannula guide). The present study was designed to examine whether such a parenchymal damage can trigger SD.Methods: Experiments were performed in awake freely moving rats with simultaneous video-monitoring of behavior and recording of SD-related DC potentials in the cortex and striatum. A parenchymal damage was produced by 1-mm protruding of thin (0.3-mm diameter) cannula beyond the tip of cannula guide preliminary implanted into the amygdala or deep cortical layers.Results: We found that the micro-injury of the brain parenchyma the volume of which did not exceed 0.3 mm3 was sufficient to initiate SD in a very high proportion of rats (75-100%). The amygdala showed increased resistance against the injury-induced SD compared to the cortex. We further showed that SD triggered by the local micro-injury invaded remote intact regions of the cortico-striatal system and evoked specific changes in spontaneous animal behavior.Discussion: The findings indicate that SD may represent a previously unidentified side effect of local parenchymal injury during site-specific microinjections and stereotactic surgery.